Centrosomes play a crucial role in the equal segregation of chromosomes by contributing to bipolar spindle assembly during mitosis (Doxsey, S. (2001) Nat Rev Mol Cell Biol 2:688-698). The tight control on centrosome duplication, limiting it to once per cell cycle, ensures that normal cells enter mitosis with two centrosomes or microtubule organizing centers (MTOCs). Failure to properly control centrosome number and function can lead to multipolar spindles, aneuploidy, disruption of cell polarity, and failure of asymmetric cell divisions (Heneen, W. K. (1970) Chromosoma 29:88-117; Nigg, E. A. (2002) Nat Rev Cancer 2:815-825).
Increased centrosome number, often termed centrosome amplification, is a common characteristic of solid and hematological cancers. Centrosome amplification correlates with aneuploidy and malignant behavior in tumor cell lines, mouse tumor models, and human tumors (D'Assoro, A. B. et al. (2002) Breast Cancer Res Treat 75: 25-34; Giehl, S. et al. (2005) Leukemia 19:1192-1197.; Levine, D. S. et al. (1991) Proc Natl Acad Sci USA 88:6427-6431; Lingle, W. L. et al. (1998) Proc Natl Acad Sci USA 95:2950-2955; Pihan, G. A. et al. (2003) Cancer Res 63:1398-1404). Mutation or misregulation of a variety of tumor suppressors or oncogenes are correlated with centrosome amplification (Fukasawa, K. (2007) Nat Rev Cancer 7:911-924). Centrosome amplification can, in principle, arise from several types of cell division errors: centrosome overduplication, de novo synthesis of centrosomes, cell fusion, or cytokinesis failure (Boveri, T. (1929) The Origin of Malignant Tumors (Baltimore: Williams and Wilkins); Ganem, N. J. et al. (2007) Curr Opin Genet Dev 17:157-162; Nigg, E. A. (2002) Nat Rev Cancer 2:815-825).
The role of supernumerary centrosomes in tumor biology is likely to be multifaceted. Whereas multiple centrosomes might facilitate tumorigenesis by promoting aneuploidy and/or disrupting cell polarity, they may also impose a fitness cost on the growth of mature cancers because of the potential for multipolar mitoses. To circumvent this problem, many cancer cells appear to have mechanisms that suppress multipolar mitoses, the best studied being clustering of supernumerary centrosomes into two groups enabling a bipolar mitosis (Brinkley, B. R. (2001) Trends Cell Biol 11:18-21; Nigg, E. A. (2002) Nat Rev Cancer 2:815-825; Ring, D. et al. (1982) J Cell Biol 94:549-556).
Centrosome clustering in tumor cells is incompletely understood, however, it is expected to rely to a significant degree on microtubule-associated proteins (MAPs) and motors that organize the spindle poles (Karsenti, E. and Vernos, I. (2001) Science 294:543-547; Nigg, E. A. (2002) Nat Rev Cancer 2:815-825). For example, recent work uncovered a requirement of cytoplasmic dynein, a minus end-directed microtubule (MT) motor, and NuMA, a spindle associated MAP, in centrosome clustering (Quintyne, N. J. et al. (2005) Science 307:127-129). The existence of mechanisms that suppress multipolar mitoses raises the possibility of a novel therapeutic strategy for cancer: drugs that interfere with centrosome clustering mechanisms could be lethal to tumor cells containing multiple centrosomes, but potentially spare normal cells. Although several drugs, including Taxol, can promote multipolar mitosis, none are specific for cells with multiple centrosomes (Chen, J. G. and Horwitz, S. B. (2002) Cancer Res 62:1935-1938; Rebacz, B. et al. (2007) Cancer Res 67:6342-6350).
Accordingly, identification of components involved in the centrosome clustering mechanisms in tumor cells is still needed.